PT  - JOURNAL ARTICLE
AU  - Moorthy, Bhagavatula
TI  - Persistent Expression of 3-Methylcholanthrene-Inducible Cytochromes P4501A in Rat Hepatic and Extrahepatic Tissues
DP  - 2000 Jul 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 313--322
VI  - 294
IP  - 1
4099  - http://jpet.aspetjournals.org/content/294/1/313.short
4100  - http://jpet.aspetjournals.org/content/294/1/313.full
SO  - J Pharmacol Exp Ther2000 Jul 01; 294
AB  - We reported earlier that 3-methylcholanthrene (MC) persistently induces hepatic ethoxyresorufinO-deethylase activities (CYP1A1) in rats for up to 45 days. In this investigation, we tested the hypotheses that persistent expression of CYP1A1 activities is paralleled by sustained induction of CYP1A1/CYP1A2 apoproteins and their mRNAs and that this phenomenon is mediated by mechanisms other than retention of MC in the rat. Rats were given MC (93 μmol/kg) i.p., once daily for 4 days, and CYP1A1/1A2 parameters were measured in liver at selected time points. MC-elicited increases in CYP1A1/1A2 activities, apoprotein contents, and mRNA levels were sustained for several weeks after the last dose of MC treatment. MC also caused long-term induction of CYP1A1 in lungs and mammary glands. Rats treated with [3H]MC once daily for 4 days excreted 92.3% of the administered radioactivity in feces and urine by day 15. The intrahepatic concentration of MC at the 15-day time point was 270 pmol/g. Dose-response studies showed that administration of MC (2 μmol/kg), which produced an intrahepatic concentration of 271 pmol/g after 24 h, did not induce CYP1A1/1A2 activities, strongly suggesting that the sustained induction of CYP1A1/1A2 was not due to retention of the parent MC in the body. Electrophoretic mobility shift assays revealed that persistent CYP1A1 induction by MC involved Ah receptor-independent mechanisms. In conclusion, our results support the hypothesis that persistent expression of CYP1A1/1A2 by MC is mediated by mechanisms independent of the retention of the parent carcinogen. The American Society for Pharmacology and Experimental Therapeutics